Factors associated with local and distant recurrence and survival in patients with resected nonsmall cell lung cancer

Authors


Abstract

BACKGROUND:

This study assessed the impact of surgical, histopathologic and patient-related factors on the risks of local and distant recurrence and overall survival for patients with stages I through IIIA nonsmall cell lung carcinoma (NSCLC) undergoing definitive resection with or without adjuvant chemotherapy.

METHODS:

This study included 373 consecutive patients treated between 2000 and 2005 who did not receive adjuvant or neoadjuvant radiotherapy, had at least 3 months of follow-up, and did not have a history of other cancers within 5 years of the diagnosis of their NSCLC. Of these, 52% had pathologic stage IA disease, 30% had stage IB, 5% had stage IIA, 8% had stage IIB and 5% had stage III disease. Forty-four patients received chemotherapy.

RESULTS:

The median follow-up was 33 months. Local failure rates at 2 years, 3 years, and 5 years were 16%, 22%, and 32%, respectively; distant recurrence rates were 13%, 15%, and 21%, respectively. Multivariable analysis revealed that local recurrence was significantly associated with the presence of lymphatic or vascular invasion (LVI), the use of chemotherapy, and having diabetes; distant recurrence was significantly higher in patients with nonsquamous cell histology, those undergoing pneumonectomy, and those with more advanced TNM stage. Survival was significantly associated with age, history of myocardial infarction, performance of a pneumonectomy, histology, LVI, and the number of positive N1 lymph nodes.

CONCLUSIONS:

Local recurrence was the predominant type of failure in this series. Patient with diabetes or LVI may benefit from close surveillance and aggressive therapy of asymptomatic local recurrences, especially when chemotherapy is given in addition to surgery. Cancer 2009. © 2009 American Cancer Society.

Lung cancer is the world's most common and deadliest form of cancer (1.35 million of 10.9 million new cases and1.18 million of 6.7 million cancer-related deaths each year).1 Approximately 75% of patients with bronchogenic carcinoma have nonsmall cell lung cancer (NSCLC). Forty-five percent of patients with NSCLC present with disease sufficiently limited in presentation to permit surgical resection.2 An increasing proportion of such patients receive adjuvant chemotherapy.3-8 However, to our knowledge, there are few data regarding the patterns of recurrence and their risk factors in this population, particularly for individuals not receiving radiotherapy.5 We therefore chose to investigate outcome in nonirradiated patients with resected NSCLC who may or may not have received adjuvant chemotherapy in relation to patient, treatment, and histopathologic characteristics.

MATERIALS AND METHODS

This retrospective study was conducted with approval of the institutional review boards of the Beth Israel Deaconess Medical Center, Boston and the Denver Department of Veterans Affairs hospitals. The medical records of all patients undergoing potentially curative resection of NSCLC from 2000 through 2005 were reviewed. Patients were included in the study population if they had postoperative follow-up of at least 3 months, no second primary cancer within 5 years of the index lung cancer, and no neoadjuvant or adjuvant radiotherapy.

A total of 373 patients met these criteria. The pathologic stage of disease was IA for 194 patients (52%), stage IB for 113 patients (30%), stage IIA for 17 patients (5%), stage IIB for 30 patients (8%), and stage III for 19 patients (5%). Clinical stage was not evaluated in our study. Of the 373 eligible patients, 44 (12%) received chemotherapy (7 neoadjuvant and 37 adjuvant) with carboplatin and paclitaxel (34 patients), cisplatin and navelbine (2 patients), cisplatin and etoposide (3 patients), other cisplatin-containing regimens (3 patients), or other regimens (2 patients). The number (and proportion) of patients in each stage receiving chemotherapy were as follows: stage IA, 7 (3.6%); stage IB, 14 (12.4%); stage IIA, 4 (23.5%); stage IIB, 9 (30.0%); and stage III, 10 (52.6%). A total of 402 patients were potentially eligible for our study at Beth Israel Deaconess Medical Center, of whom 229 patients were eligible after excluding 121 patients with inadequate follow-up, 44 patients with second cancers, and 8 patients who were treated with postoperative radiotherapy. Sixty-two patients were included from the Denver Veterans Administration (VA) hospital, after excluding 2 patients who received surgery at another hospital, 7 patients with inadequate follow-up, 11 patients with second cancers, 3 patients who received postoperative radiotherapy, 9 patients who did not receive surgery, and 1 patient with an incorrect pathologic diagnosis. Eighty-two patients were included from the Boston, VA after excluding 8 patients with inadequate follow-up, 13 patients with second cancers, 4 patients who received postoperative radiotherapy, 9 patients who did not receive surgery, and 1 patient with an incorrect pathologic diagnosis.

Patient-related factors recorded included the following: age; weight loss; preoperative hemoglobin; body mass index (BMI); presenting symptoms (cough, hemoptysis, dyspnea, or none); pulmonary function test results (forced expiratory volume at 1 second [FEV1], FEV1%, and diffusion capacity of lung for carbon monoxide); smoking status (never, quit >2 years ago, quit between 1-2 years ago, quit 6 months to 1 year ago, quit 30 days to 6 months before surgery, or smoking at present); drinking of alcoholic beverages (never, quit >2 years ago, quit between 1-2 years ago, quit 6 months to 1 year ago, quit 30 days to 6 months before surgery, drinking at present); number of drinks per week; chronic use of steroids; history of intercurrent illnesses (diabetes, hypertension, myocardial infarction, coronary artery disease, cardiac rhythm disturbance, coronary artery bypass graft, cerebrovascular accidents, renal failure, thromboembolic disease); performance of a staging positron emission tomography (PET)-computed tomography (CT) at diagnosis; medication use at diagnosis (aspirin, statins, and nonsteroidal anti-inflammatory drugs); and hemoglobin and albumin values within 30 days of surgery. Surgically-related factors included: surgical time; fluid balances during surgery (urine output, estimated blood loss, fluids infused, total excess intraoperative fluids assuming 1 unit of packed red blood cells to be 300 cc); transfusions (total number U required within 90 days of surgery, number of U required within the first day, number of U required within 2-4 days, and number required after 4 days); type of resection (wedge resection, segmentectomy, lobectomy/bilobectomy, pneumonectomy); type of lymph node staging procedure; intraoperative and postoperative complications (pulmonary infection or pneumonia, adult respiratory distress syndrome, arrhythmias and their type [supraventricular tachycardia, ventricular tachycardia, or nonspecific ones], fistula formation, stump leak, prolonged air leak, anastomosis leak, mediastinitis/empyema, myocardial infarction, death, pulmonary embolus, deep venous thrombosis, and brachial plexus injury); length of hospital stay; and surgeon. Histopathologic factors included the following: tumor size; tumor grade; results and performance of previous fine-needle aspiration biopsy; lymphatic or vascular invasion (LVI); perineural invasion; surgical margin status; extracapsular lymph node involvement; details of lymph node resection (number resected, number positive, lymph node level resected, lymph node level involvement, number of N1 lymph nodes resected, number of N1 lymph nodes positive, number of N2 lymph nodes resected, number of N2 lymph nodes positive, lymph node level involved, number of lymph node stations sampled at mediastinoscopy, number of lymph node stations examined during resection); lymph node density (defined as the total number of positive lymph nodes divided by the total number of recovered lymph nodes); histology (NSCLC not otherwise specified, squamous cell, adenocarcinoma, large cell carcinoma, neuroendocrine carcinoma, brochioloalveolar cancer [BAC], adenocarcinoma with bronchioloalveolar features); tumor lobe location; invasion of pleura; invasion of the diaphragm; invasion of the mediastinum; and involvement of the chestwall. Details of chemotherapy recorded included the following: type of chemotherapy (carboplatin and paclitaxel, cisplatin and navelbine, cisplatin and etoposide, other cisplatin-containing regimens, gemcitabine-containing combinations, other regimen), treatment sequencing (giving chemotherapy preoperatively, postoperatively, or both); and number of cycles.

Patterns of failure were determined using physician clinical assessment, radiographic reports and/or review of imaging studies. Patients were scored as having a recurrence when a new or enlarging lymph node measured >1 cm in short axis on follow-up CT. For patients who underwent PET at the time of disease recurrence, all sites of abnormal uptake that correlated with a lymph nodes or soft tissue mass were scored, regardless of size. When available, data from bronchoscopy, biopsy, or mediastinoscopy were used to supplement the radiographic findings.

Only the first sites of disease recurrence were scored. Patients with simultaneous local and distant failures were scored as having both types of failure for both univariate and multivariable analyses. We followed the Lung Cancer Study Group in scoring both ipsilateral pulmonary and mediastinal recurrences as local recurrences.9 Contralateral lymph node recurrences were also included in this category because of the noted tendency of NSCLC to be associated with contralateral mediastinal lymph node involvement, especially for left-sided tumors.10 Ipsilateral pulmonary recurrences were only included as a local recurrence if the involved physicians were certain that this tumor was recurrent. In equivocal cases, we considered the tumor to be a second primary cancer and censored the patient from our study group. Local recurrences were defined as those occurring in the following sites: ipsilateral lung, bronchial stump or staple line, and lymph node regions (subcarinal, periesophageal, ipsilateral or contralateral mediastinum, supraclavicular, or hilar lymph nodes). Distant failures were defined as those occurring in the liver, contralateral lung, adrenal glands, brain, bone, or other locations.

Recurrence and survival rates at 2 years, 3 years, and 5 years were calculated by the Kaplan-Meier method.11 Cox proportional hazards regression was performed to assess the impact of possible risk factors for local and distal recurrence.12

RESULTS

The median follow-up was 33 months (range, 4 months–98 months). The characteristics of the population with regard to selected patient-related, treatment-related, and histopathologic factors are detailed in Tables 1 through 3.

Table 1. Distribution of Patient Factors and Patterns of Failure*
VariableNo. (%)*Local Failure No. (%)Distant Failure No. (%)Simultaneous Local and Distant Failure No. (%)No Failure No. (%)
  • Hgb indicates hemoglobin; BMI, body mass index.

  • *

    Frequency and percentages based on a total number of patients of 373. Pattern of failure columns based on a total number of patients of 372 due to 1 patient with known failure, but unknown whether local or distant.

No. of patients373 (100)61 (16)34 (9)25 (7)252 (68)
Median age, y7069687270
Median Hgb, g/dL13.5013.5013.6513.4013.60
BMI
 <2026 (7)3 (12)3 (12)2 (8)18 (69)
 20-25104 (28)15 (14)13 (12)3 (3)73 (70)
 25.1-30128 (34)23 (18)8 (6)14 (11)82 (65)
 >3067 (18)13 (19)6 (9)2 (3)46 (69)
 Unknown48 (13)7 (15)4 (8)4 (8)33 (69)
Cough
 No259 (69)45 (17)17 (7)15 (6)181 (70)
 Yes114 (31)16 (14)17 (15)10 (9)71 (62)
Hemoptysis
 No325 (87)56 (17)26 (8)22 (7)220 (68)
 Yes48 (13)5 (10)8 (17)3 (6)32 (67)
Smoking
 Never21 (6)4 (19)1 (5)1 (5)15 (71)
 Quit ≥2 y160 (43)28 (18)11 (7)14 (9)107 (67)
 Quit <2 y47 (13)3 (6)7 (15)3 (6)34 (72)
 Current smoker115 (31)22 (19)14 (12)6 (5)73 (63)
 Unknown30 (8)4 (14)1 (3)1 (3)23 (79)
Diabetes
 No306 (82)43 (14)29 (9)19 (6)215 (70)
 Yes66 (18)18 (28)5 (8)6 (9)36 (55)
 Unknown1 (0.3)0 (0)0 (0)0 (0)1 (100)
Table 2. Distribution of Treatment Factors and Patterns of Failure
VariableNo. (%)*Local Failure No. (%)Distant Failure No. (%)Simultaneous Local and Distant Failure No. (%)No Failure No. (%)
  • *

    Frequency and percentages based on a total number of patients of 373. Pattern of failure columns based on a total number of patients of 372 due to 1 patient with known failure, but unknown whether local or distant.

No. of patients373 (100)61 (16)34 (9)25 (7)252 (68)
No. of positive lymph nodes
 0302 (81)46 (15)22 (7)21 (7)212 (70)
 123 (6)6 (26)4 (17)2 (9)11 (48)
 ≥222 (6)4 (18)5 (23)013 (59)
 Not sampled26 (7)5 (19)3 (12)2 (8)16 (62)
Median no. of resected N1 lymph nodes323.533
Median no. of resected N2 lymph nodes21332
No. of positive N1 lymph nodes
 0300 (80)44 (15)23 (8)20 (7)212 (71)
 120 (5)6 (30)4 (20)2 (10)8 (40)
 ≥222 (6)5 (23)4 (18)013 (59)
 Not sampled26 (7)5 (19)3 (12)2 (8)16 (62)
 Unknown5 (1)1 (20)01 (20)3 (60)
No. of positive N2 lymph nodes
 0360 (97)59 (16)30 (8)24 (7)246 (69)
 ≥18 (2)1 (12)4 (50)03 (38)
 Unknown5 (1)1 (20)01 (20)3 (60)
Mean lymph node density0.040.040.070.010.04
Mean lymph node density in patients staged0.020.040.050.010.02
Resection
 Wedge/segment49 (13)12 (25)1 (2)1 (2)34 (71)
 Wedge/segment NX24 (6)5 (21)3 (12)2 (8)14 (58)
 (Bi)Lobectomy276 (74)42 (15)20 (7)22 (8)192 (70)
 Pneumonectomy24 (6)2 (8)10 (42)012 (50)
Chemotherapy
 No328 (88)50 (15)27 (8)23 (7)227 (69)
 Yes44 (12)11 (25)7 (16)2 (5)24 (55)
 Unknown1 (0.3)0001 (100)
Table 3. Distribution of Histopathologic Factors and Patterns of Failure
VariableNo. (%)*Local Failure No. (%)Distant Failure No. (%)Simultaneous Local and Distant Failure No. (%)No Failure No. (%)
  • LVI indicates lymphatic or vascular invasion; BAC, bronchoalveolar carcinoma.

  • *

    Frequency and percentages based on a total number of patients of 373. Pattern of failure columns based on a total number of patients of 372 due to 1 patient with known failure, but unknown whether local or distant.

Grade
 Well67 (18)10 (15)2 (3)3 (4)52 (78)
 Well to moderate143 (38)27 (19)12 (8)11 (8)92 (65)
 Moderate to poor36 (10)5 (14)4 (11)4 (11)23 (64)
 Poor to undifferentiated100 (27)17 (17)14 (14)6 (6)63 (63)
 Unknown27 (7)2 (7)2 (7)1 (4)22 (81)
LVI
 No318 (85)43 (14)27 (9)22 (7)225 (71)
 Yes55 (15)18 (33)7 (13)3 (5)27 (49)
Pleural invasion
 None303 (81)48 (16)27 (9)17 (6)210 (70)
 Present70 (19)13 (19)7 (10)8 (11)42 (60)
Location
 Right upper134 (36)18 (13)7 (5)6 (4)103 (77)
 Right middle21 (6)4 (19)2 (10)4 (19)11 (52)
 Right lower55 (15)14 (25)4 (7)6 (11)31 (56)
 Left upper93 (25)14 (15)14 (15)5 (5)59 (64)
 Left lower51 (14)6 (12)2 (4)3 (6)40 (78)
 Main bronchus5 (1)1 (20)1 (20)03 (60)
 Unknown14 (4)4 (29)4 (29)1 (7)5 (36)
Stage
 IA194 (52)27 (14)11 (6)12 (6)143 (74)
 IB113 (30)21 (19)10 (9)6 (5)76 (67)
 IIA17 (5)7 (41)1 (6)09 (53)
 IIB30 (8)3 (10)9 (30)4 (13)14 (47)
 IIIA-B19 (5)3 (16)3 (16)3 (16)10 (53)
T classification
 T1213 (57)34 (16)14 (7)12 (6)152 (72)
 T2135 (36)24 (18)16 (12)8 (6)87 (64)
 T3-425 (7)3 (12)4 (16)5 (20)13 (52)
N classification
 N0301 (81)45 (15)22 (7)21 (7)212 (71)
 N1-246 (12)11 (24)9 (20)2 (4)24 (52)
 NX26 (7)5 (19)3 (12)2 (8)16 (62)
Histology
 Squamous109 (29)23 (21)8 (7)5 (5)72 (67)
 Adenocarcinoma137 (37)19 (14)15 (11)12 (9)91 (66)
 Large cell25 (7)3 (12)2 (8)3 (12)17 (68)
 BAC28 (8)3 (11)01 (4)24 (86)
 Adenocarcinoma-BAC46 (12)7 (15)3 (7)2 (4)34 (74)
 Other27 (7)6 (22)6 (22)2 (7)13 (48)

There were 61 patients (16%) who had local disease recurrence only as the first site of failure, 34 patients (9%) who had distant failure only, and 25 patients (7%) who had simultaneous local and distant failure. One patient had a known failure, but it was unknown whether it was local or distant. The most common sites of local disease recurrence were the ipsilateral lung (52%), ipsilateral mediastinum (29%), and the bronchial stump or staple line (21%). The most common sites of distant disease recurrence were the contralateral lung (34%), bone (29%), and the brain (25%). The crude rates of the different failures are given in relation to individual factors in Tables 1 through 3.

The actuarial local failure rates at 2 years, 3 years, and 5 years were 16%, 22%, and 32%, respectively. On univariate analysis, factors were associated with a higher risk of local control with a P ≤ .1 were (with their corresponding P and hazards ratios [HRs]): diabetes (P = .0080; HR of1.895); use of chemotherapy (P = .0302; HR of 1.934); presence of LVI (P = .0001; HR of 2.621); past myocardial infarction (P = .0929; HR of 1.66); pN1 (P = .0004; HR of 8.542); undergoing lymph node staging at the same time as resection of the primary tumor (P = .0558; HR of 0.618); preoperative positive fine-needle aspiration versus no preoperative fine–needle aspiration (P = .0513; HR of 1.686); preoperative negative fine-needle aspiration versus no preoperative fine-needle aspiration (P = .0164; HR of 2.80); T1N1 versus T1N0 or T1NX disease (P = .0548; HR of 2.202); and1 positive N1 lymph node versus 0 (P = .0520; HR of 2.075). These factors were all included in a multivariable proportional hazards regression model, and backward selection was used. Using a statistical significance criterion of P value <.05, 3 factors remained in the model of local recurrence: LVI (P = .0002; HR of 2.543); diabetes (P = .0140; HR of 1.812); and use of chemotherapy (P = .0262; HR of 1.972). The actuarial risks of local disease recurrence in relation to these factors are shown in Figure 1.

Figure 1.

Local recurrence rate in relation to the presence or absence of (Top) diabetes, (Middle) lymphatic or vascular invasion (LVI), and (Bottom) use of chemotherapy (chemo). Surg indicates surgery.

Sites of local failure were further examined for patients with these adverse risk factors. For patients with LVI, local failures occurred in the ipsilateral lung or bronchial stump (52%), the ipsilateral mediastinum (38%), contralateral lymph node areas (29%), and ipsilateral supraclavicular areas (14%). The respective proportions for patients with diabetes were 71%, 33%, 25%, and 4%, respectively; for patients treated with chemotherapy, the proportions were 69%, 38%, 8%, and 0%, respectively.

The actuarial distant recurrence rates at 2 years, 3 years, and 5 years were 13%, 15%, and 21%, respectively. Factors found to be associated with this risk in univariate analyses, with a P value ≤ .1, were as follows: cough (P = .0102; HR of 1.958); the presence of an asymptomatic nodule (P = .0436; HR of 0.584); the use of transfusion (P = .0537; HR of 2.085); perineural invasion (P < .0001; HR of 21.56); weight loss (P = .0796; HR of 1.024); tumor size (P = .0446; HR of 1.12); pneumonectomy (P < .0001; HR of 4.440); “other” histology versus squamous (P = .0116; HR of 3.115); stage IIB versus IA disease (P <.0001; HR of 4.269); stage IIIA or IIIB versus IA disease (P = .022; HR of 2.86); T3 or T4 versus T1 (P = .0017; HR of 3.376); 1 positive N1 lymph node versus 0 (P = .0561; HR of 2.303); and ≥1 positive N2 lymph nodes versus 0 (P = .0017; HR of 5.135). Those factors found to remain statistically significant (P < .05) in a multivariable proportional hazards regression model of distant recurrence included: nonsquamous cell histology in comparison to squamous cell histology (P = .0412; HR of 1.961), stage IIB versus IA disease (P = .0025; HR of 3.358), stage IIIA or B versus IA disease (P = .0186; HR of 2.956), and performance of a pneumonectomy compared with lesser surgery (P = .0039; HR of 3.252). Actuarial risks of distant failure in relation to these factors are shown in Figure 2.

Figure 2.

Distant recurrence in relation to (Top) histology and (Bottom) type of resection. Pneumo indicates pneumonectomy.

The actuarial rates of overall survival at 2 years, 3 years, and 5 years were 85%, 76%, and 57% respectively. Factors associated with overall survival, with a P value ≤ .1, in univariate analyses included: performing a wedge resection before definitive resection (P = .0972; HR of 0.672); LVI (P = .0001; HR of 2.309); history of myocardial infarction (P = .017; HR of 1.816); history of coronary artery disease (P = .0151; HR of 1.592); history of myocardial infarction, coronary artery disease, or thromboembolism (P = .0058; HR of 1.651); transfusion (P = .0225; HR of 1.917); lymph node staging at the time of resection (P = .0805; HR of 0.700); age (P = .0009; HR of 1.033); lymph node density (P = .0575; HR of 4.146); lymph node density including those lymph nodes retrieved with lymph node staging (P = .0196; HR of 11.956); pneumonectomy (P = .0004; HR of 2.856); squamous versus bronchioloalveolar histology (P = .042; HR of 2.433); squamous versus adenocarcinoma with bronchioloaveolar features (P = .003; HR of 4.049); pathologic N0 versus no lymph node sampling; (P = .0396; HR of 0.53); 1 versus 0 positive lymph nodes (P = .007; HR of 2.226); 1 positive N1 lymph node versus 0 (P = .0016; HR of 2.549); NX versus 0 positive N1 lymph nodes (P = .0393; HR of 1.891); ≥1 versus 0 positive N2 lymph nodes (P = .0206; HR of 2.901); and NX versus 0 positive N2 lymph nodes (P = .0528; HR of 1.811). Multivariable proportional hazards regression revealed that 6 factors were significantly associated (P < .05) with patient survival: LVI (P = .0019; HR of 2.006); past myocardial infarction (P = .0123; HR of 1.914); performance of a pneumonectomy (P = .0018; HR of 2.793); squamous cell histology versus adenocarcinoma with bronchioloaveolar features (P = .0199; HR of 3.040); age as a continuous variable (P = .0012; HR of 1.034); having 1 positive N1 lymph node versus 0 (P = .0018; HR of 2.656); and NX versus no positive N1 lymph nodes on pathologic staging (P = .0181; HR of 2.138). Actual risks of survival in relation to these factors can been seen in Figure 3.

Figure 3.

Overall survival in relation to (Top) histology, (Middle) number of positive N1 lymph nodes, and (Bottom) presence or absence of lymphatic or blood vessel invasion. Adeno indicates adenocarcinoma, BAC, bronchioloalveolar cancer; LVI, lymphatic or vascular invasion.

DISCUSSION

The purpose of our investigation was to determine the incidence, patterns of failure, and risk factors associated with increased risks of local and/or distant recurrences for patients with resected NSCLC who were not receiving radiotherapy. The risk of local recurrence in this population was higher than the risk of distant recurrence. Of importance, the factors associated with increased local and distant recurrence rates were different from each other.

LVI was associated with the highest HR for local disease recurrence. The poor prognostic impact of LVI has been previously noted with regard to both recurrence and survival in patients undergoing definitive resection.13, 14 However, it was surprising to find that the presence of diabetes at diagnosis and the administration of chemotherapy were associated with significantly increased risks for local disease recurrence. To the best of our knowledge, this is the first time that such findings have been reported.

Three recent phase 3 trials demonstrated that adjuvant cisplatin-based chemotherapy improves survival in non-Asian patients with NSCLC.3-5 Although all 3 trials included patients with stage I disease, chemotherapy was only found to have a significant survival benefit in patients with stages II or III lung cancer.

A fourth trial indicated a survival benefit for adjuvant chemotherapy in stage I NSCLC when first reported, but with longer follow-up, there was no significant difference noted with regard to 5–year overall survival.6 Unfortunately, 5-year disease-free survival rates were not reported. These negative results may have been due to the use of carboplatin-based chemotherapy (instead of cisplatin-based chemotherapy), the lack of power in the study, and/or a true lack of benefit of adjuvant chemotherapy in stage I patients.7 However, the results of the current study suggest another possible explanation for their findings, namely that chemotherapy may eliminate micrometastatic disease, but not residual local disease, hence resulting in an increased risk of local failure as the first site of recurrence, with no overall change in outcome.

Obesity has been associated with both an increased incidence of disease recurrence and an increased risk of death from many different cancers.18, 19 It has been speculated that hyperinsulinema can lead to increased growth rates for malignant tumors, which often overexpress insulin–like growth factor 1 (IGF-1) and insulin receptors.20-24 In the current series, multivariable analysis demonstrated that diabetes, but not BMI was associated with local recurrence. Furthermore, there was no significant association noted between the presence of diabetes and BMI (data not shown). Of interest, diabetes did not increase the risk of distant failure. A recent study reported that male diabetics taking thiazolides (pioglitazone and rosiglitazone) had a reduced risk of developing lung cancer, but not prostate or colon cancer.25 The thiazolides result in decreased expression of the antiapoptotic, immunosuppressive, and inflammatory prostaglandin E2 in NSCLC cell lines.26 Furthermore, recent evidence suggests that the antihyperglycemic drug metformin may have therapeutic effects against pancreatic cancer cell lines and breast cancer.27, 28 However, we do not have data regarding the medications our diabetic patients were taking and hence this hypothesis would need to be tested in a larger population of diabetics where such information is available.

In the current study, distant failure was significantly associated with nonsquamous cell histology, tumor stage, and the performance of a pneumonectomy. Some investigators have also shown that patients with squamous cell histology have a lower risk of distant metastases,29 whereas others have not.30 Stage is reported to be a powerful prognostic determinant for disease recurrence and survival in other series also.31, 32 A past retrospective review found that patients treated with a sleeve resection had lower recurrence rates and higher survival than patients undergoing a pneumonectomy.33 However, the true meaning of our finding is uncertain, in part due to the limited number of patients undergoing a pneumonectomy (only 24) and the possibility that the need to perform a pneumonectomy is a surrogate for tumor-related factors that are not captured completely by tumor stage or other conventional prognostic factors.

Overall survival in the current series was significantly impacted by histology, with patients with adenocarcinoma with BAC features having a better survival than patients with squamous cell carcinoma. This result is consistent with a previous retrospective study we performed that demonstrated different patient and tumor characteristics and better survival in patients who underwent resection for lymph node-positive BAC.34 We believe that number of positive N2 lymph nodes did not demonstrate significance in our multivariable model because of the few patients with such N2 involvement. Of the significant factors for local recurrence, only LVI was also found to be associated with a survival decrement. We believe this may be related to patients with LVI having a greater incidence of disease recurrence in local sites that may have been difficult to salvage (contralateral mediastinal and supraclavicular lymph nodes) than for other patients with local recurrence.

It should be noted that in an earlier analysis (before including patients from 2005) diabetes was associated with an increased HR for local recurrence, with a lower P value than reported in the current study.35 The median follow-up time of that study was 37 months, compared with 33 months for the current study. We believe that the role of diabetes may be noted more clearly as patients are followed for longer periods.

The findings of the current study have implications for patient follow-up. Patients with local recurrences can often be long-term survivors after undergoing salvage therapy, especially when disease recurrences are detected while they are asymptomatic.36-38 Hence, patients with increased risks of local recurrence might benefit from more intensive follow-up schedules or regimens. The National Comprehensive Cancer Network currently recommends that lung cancer patients undergo contrast-enhanced CT and clinical examinations every 4 months to 6 months during the first 2 years after treatment and then annually.39 We believe that our findings suggest patients who were treated with chemotherapy and/or who had diabetes at the time of diagnosis may require more frequent follow-up in the subsequent years as well.

Conclusions

Local disease recurrence was the predominant pattern of failure in the current series of consecutive patients treated by resection with or without chemotherapy. Different factors were found to be related to the risks of local and distant failure. Diabetes and the presence of LVI were found to be significantly associated with an increased risk of local failure. Because some patients with asymptomatic local recurrences may benefit from aggressive therapy, such patients might benefit from close surveillance, especially when chemotherapy is given in addition to surgery. Additional studies should be performed to confirm these findings.

Conflict of Interest Disclosures

The authors made no disclosures.

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